Department of Neurobiology, and Department of Ophthalmology of the First Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Department of Pharmacology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Nat Commun. 2019 Mar 13;10(1):1193. doi: 10.1038/s41467-019-09114-z.
Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer's disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP) in axons. Selectively inhibiting Aβ-induced PIP hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP pathway whereby oligomeric Aβ induces early synaptic deficits in AD.
淀粉样蛋白β (Aβ) 寡聚体诱导的神经递质释放异常被认为是导致阿尔茨海默病 (AD) 突触功能障碍的关键早期事件。在本研究中，我们报告在具有升高的 Aβ产生的 AD 小鼠模型中，突触间的释放概率 (Pr) 在早期阶段显著降低。高纳摩尔合成寡聚 Aβ也会抑制野生型小鼠中 SC-CA1 突触的 Pr。这种 Aβ 诱导的 Pr 抑制主要是由于 mGluR5 介导的轴突中磷脂酰肌醇-4,5-二磷酸 (PIP) 的耗竭。选择性抑制海马 CA3 区中 Aβ 诱导的 PIP 水解强烈阻止了 SC-CA1 突触中寡聚 Aβ诱导的 Pr 抑制，并挽救了 APP/PS1 小鼠的突触和空间学习记忆缺陷。这些结果首次揭示了 Aβ 寡聚体诱导 AD 早期突触缺陷的突触前 mGluR5-PIP 途径。
